Despite technological advances in surgery and radiotherapy for patients who suffer from oral squamous cell carcinoma (OSCC), the survival rate has remained un-improved during the last two decades indicating our ability to treat patients has reached a plateau. We have reported that proteasome inhibition induced ER stress CHOP-mediated apoptosis in HNSCC cell lines, including several that are cisplatin-resistent. ER stress leads to a physiological response known as the unfolded protein response (UPR) which consists of distinct parallel genetic programs that attempt to restore homeostatic protein folding or lead to apoptosis if the stress is prolonged or robust. We hypothesized that we could use high throughput screening (HTS) with diverse chemical libraries to identify novel small molecule CHOP activators to induce apoptosis in OSCC cells. We have developed a Complementary cell-based assay using stably transfected CMQ-K1 cells that individually report on the PERK/elF2D/CH0P (apoptotic) and the IRE1/XBP1 (adaptive) pathways of the UPR. Identifying compounds that specifically activate only PERK/elF2n/CHOP and not 1RE1/XBP1 has allowed us to aile out many compounds that generally perturb protein folding. 65 hit compounds have been identified that activated the CHOP but not the XBP1 reporter with chemical signatures amenable for synthetic analoging and therapeutic development. We propose to test the ability of these 65 Compounds along with commercially available analog series to induce CHOP expression and apoptosis in a panel of OSCC cells. The hiost promising candidates will be evaluated in vivo in a well-characterized rbd^ht xenograft model. The long-term objectives of the proposed studies are to elucidate the ability of these novel small molecules to induce CHOP and inhibit growth or induce apoptosis in OSCC cells and to further screen very large diverse libraries of chemical probes with our complementary cell-based screen, Small molecule UPR agonisits identified through these studies will pfovide a convenient cost-effective rneans of treating patients suffering from a disease for which therapies are limited to minimally effective chemotherapies, damaging radiation or painful surgeries that often interfere with their ability to speak, chew or even breathe.